Mandelboum, S. | bioRxiv Science

bioRxiv2026

COUNTERING AGE-ASSOCIATED ALTERATIONS IN OLIGODENDROCYTE-DERIVED EXTRACELLULAR MATRIX REJUVENATES COGNITION

Efforts to rejuvenate age-related cognitive decline have predominantly targeted neurons, often overlooking non-neuronal cell types in the aging brain. Here, we show that countering alterations in oligodendrocyte-derived extracellular matrix (ECM) in the aging hippocampus restores cognition. We identify broad age-associated transcriptional and proteomic changes in oligodendrocytes, including dysregulation of the matrisome, with marked upregulation of ECM components and associated regulators with age. Among these, we detect an increase in Hyaluronan and proteoglycan link protein 2 (HAPLN2), an oligodendrocyte-derived core matrisome protein that locates specifically at the nodes of Ranvier, in the hippocampus of aged mice and older humans. Hapln2 overexpression in oligodendrocytes of young mice recapitulated age-related memory impairments. Conversely, abrogating the age-related increase in Hapln2 induced synaptic plasticity-related hippocampal transcriptional signatures and improved memory in aged mice. Together, these data define oligodendrocyte-derived ECM remodeling as a hallmark of brain aging that can be targeted to rescue cognitive decline.

neuroscience↗

bioRxiv2025

The Translational Landscape of Reactive Astrocytes Reveals the Impact of eIF2B-mediated Dysregulation in VWM Disease

A devastating genetic recessive neurodegenerative disorder, Vanishing White Matter Disease (VWMD), stems from mutations in eIF2B--a master regulator of mRNA translation initiation and mediator of cellular stress response. While astrocytes, the brains essential support cells, are known to be central to VWMD pathology, the molecular mechanisms underlying their dysfunction remain poorly understood. Our study reveals that even a mild mutation in eIF2B5 profoundly disrupts astrocyte mRNA translation regulation upon cytokine-mediated activation, affecting nearly one-third of all expressed genes. Through innovative integration of RNA-seq and Ribo-seq analyses using primary cell cultures of astrocytes isolated from eIF2B5R132H/R132H mice, we discovered attempts to compensate for impaired protein production by increasing mRNA levels. However, this compensation proves insufficient to maintain critical cellular functions. Our comprehensive analysis uncovered significant disruptions in cellular energy production and protein synthesis machinery. We also predicted previously unknown defects in cholesterol biosynthesis within mutant astrocytes. Moreover, a meta-analysis of translation initiation scores pinpointed, for the first time, a short list of specific effector gene candidates that may drive disease progression. This powerful combination of transcriptome and translatome illuminates the complex pathophysiology of VWMD and identifies promising new biomarkers and therapeutic target opportunities.

molecular biology↗